Erythropoietin, a cytokine made in the kidney, has proven to be effective therapy for anemia in patients with end-stage renal disease. The tissue distribution and regulation of gene expression for erythropoietin and its receptor reveal important insight on erythropoietin induction by hypoxia, on its role in mature red cell production and its activity in non-hematopoietic tissues. Erythropoietin acts primarily to regulate blood hemoglobin through the formation of mature red blood cells and binds to its receptor on the surface of erythroid progenitor cells to promote erythropoiesis by preventing apoptosis and stimulating proliferation and differentiation. We observed high-dose erythropoietin treatment in C57Bl/6 mice affects body weight, fat mass and glucose tolerance, suggesting that the pleotropic effects of erythropoietin extend to fat and glucose metabolism. We observed the erythropoietin dosage effect on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. Epo doses from 150 U/kg and higher significantly reduced body weight gain and fat mass, while, only Epo doses of 300&#8201;U/kg and higher significantly affected glucose tolerance. Epo doses up to 1000 U/kg for 5 weeks did not showed any detectable effects on food intake, and only 1000&#8201;U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment. Mice that lack erythropoietin or its receptor die in utero from severe anemia. To determine the role of endogenous erythropoietin beyond erythropoiesis, we examined mice with erythropoietin receptor expression restricted to hematopoietic tissue. These animals survived through adulthood with normalized erythroid differentiation and hematocrit, and exhibited no gross morphologic deformation. These mice exhibit an age dependent obesity with an increase in body weight up to 50% greater than that of wild type animals at 12 months. These mice eventually became insulin resistance with a significant increase in white fat. These observations suggest that endogenous erythropoietin may contribute to maintaining fat mass accumulation and provide new insight to the consequence of erythropoietin activity in non-hematopoietic cells.